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Abstract

Despite the major advancements in the management of chronic phase (CP) chronic myeloid leukemia (CML), blast crisis (BC) remains a major therapeutic challenge. BC can be myeloid, lymphoid, or mixed lineage with myeloid BC being the most common type. BC in CML is mediated by aberrant tyrosine kinase activity of the BCR::ABL fusion protein. The introduction of BCR::ABL tyrosine kinase inhibitor (TKI) has been a gamechanger in the treatment of CML and there has been a significant reduction in the incidence of BC. The main treatment goal in BC is to achieve a second CP and consolidate that with an allogeneic stem cell transplantation (SCT) in eligible patients. The outcomes in BC remain dismal even in the current era. In this review, we provide an overview of the biology and current therapeutic approach in myeloid BC.

Keywords

Chronic myeloid leukemia blast crisis tyrosine kinase inhibitor stem cell transplant additional chromosomal abnormality

Introduction

Chronic myeloid leukemia (CML) is a triphasic myeloproliferative neoplasm (MPN) characterized by reciprocal translocation between chromosome 9q34 and chromosome 22q11.2 resulting in the formation of a BCR::ABL1 oncogene. Most CML patients (85%-90%), are diagnosed in the chronic phase (CP), however, in the absence of treatment, will inevitably advance to BC.¹ BC is the most dreaded complication of CML, and it is notoriously difficult to treat. Approximately, 20% to 25% of patients may develop de novo blast crisis (BC) without the intervening accelerated phase (AP). Although BC mimics de novo acute leukemia, it is a separate clinical entity altogether characterized by resistance to standard therapy. Fortunately, the risk of transformation to BC has diminished markedly (1%-1.5% per year) in the tyrosine kinase inhibitor (TKI) era.² Most patients (70%-80%) with CML-BC present with myeloid phenotype, whereas up to one third can transform to lymphoid BC.³

The World Health Organization (WHO) defines BC as ⩾ 20% blasts in the bone marrow or peripheral blood or evidence of extramedullary disease. Clinical and laboratory features provide important clues regarding the cell lineage. Similarly, cytogenetic profile can provide additional information to differentiate the two types of BC. Mutations in TP53 and isochromosome i(17q) are more commonly seen in myeloid BC while hypodiploidy, monosomy 7, and CDKN2A mutations are frequently associated with lymphoid BC.⁴ Flow cytometry (FC) and immunohistochemistry (IHC) can help confirm the cell lineage of the BC.

Mechanism of Progression to CML Blast Crisis

The precise mechanisms involved in transformation to blast crisis (BC) remain unclear. BC is believed to be mediated by increased BCR::ABL tyrosine kinase activity that drives secondary molecular and cytogenetic changes leading to clonal evolution and differentiation arrest.^5,6 The fact that the risk of blast transformation is markedly reduced in the TKI era, further supports this theory. Mutations in TET2, ASXL1, CBL family, and IDH family are often seen in advanced phase CML with myeloid phenotype, and they highlight the aggressive nature of the disease.⁷ Also, mutations in the polycomb repressive complex have been implicated in CML progression.⁸

Management of Myeloid BC

Despite significant advancements in the management of CP-CML, BC remains a therapeutic challenge with dismal outcomes. It is critical to make the distinction between myeloid and lymphoid BC as it has important therapeutic and prognostic implications. All CML patients with newly diagnosed BC should have a detailed work up that includes complete blood counts, peripheral blood smear, immunophenotyping by FC, cytogenetics, BCR::ABL quantitative reverse transcription polymerase chain reaction (qRT-PCR), BCR::ABL kinase domain mutation and next-generation sequencing (NGS) myeloid panel. All patients who are candidates for an allogenic stem cell transplantation (SCT) should undergo a donor search and appropriate evaluation. The primary objective of treatment in patients with CML-BC is to achieve a second CP and proceed to allogenic SCT in eligible patients. In patients with CML-BC, a deep molecular response correlates with better outcomes. CML-BC patients who achieve a major molecular response (MMR) or complete cytogenetic response (CCyR) have dismal outcomes, and hence, the goal should be to achieve molecularly undetectable leukemia.⁹ Several important factors, such as age, comorbidities, performance status, de novo versus progression on TKI, BCR::ABL kinase mutations have to be considered prior to selecting therapy for myeloid BC. Historically, single-agent cytarabine and combinations with idarubicin have been used with some degree of success, but remissions were often short lived.^10,11

Single-Agent TKI in CML Myeloid BC

In CP-CML, BCR::ABL is the sole driver mutation, whereas, most patients (50%-80%) with BC tend to have additional cytogenetic alterations (ACAs) making them genetically complex. Unlike in CP-CML, single-agent TKI therapy (including third generation) are overall less effective in BC with responses being transient and the median survival is less than 1 year. The TKI response in BC depends on the cell lineage and ACA. The TKI selection depends on the prior therapy and the mutational profile.^12,13 Patients with myeloid BC and ACA have a worse outcome when compared with those with lymphoid BC.¹⁴ The most commonly used TKIs in BC are listed below. Clinical trial data supporting use of all the below-listed TKIs in BC are provided in Table 1.

Table 1.

Outcomes with single-agent TKIs in CML myeloid BC.

TKI	Study	Total patients (n)	Dose (mg)	Myeloid blast crisis
				n	HR (%)	CHR (%)	CyR		Myeloid blast crisis median survival (months)
				n	HR (%)	CHR (%)	MCyR (%)	CCyR (%)	Myeloid blast crisis median survival (months)
Imatinib	Druker et al.²⁰	58	300-1000	38	55	11	12	9	NA
	Sawyers et al.²¹	229	400 or 600	229	67	15	16	7	6.9
	Kantarjian et al.²²	75	300-1000	65	52	23	11	5	6.5
	Wadhwa et al.²³	76	400	21	29	NA	NA	NA	6.5
	Palandri et al.²⁴	92	600	72	47	24	11	5	7
Nilotinib	Giles et al.²⁵	136	800	105	60	24	38	30	10.1
	Kantarjian et al.²⁶	119	50-1200	24	42	8.3	21	4.1	NA
	Nicolini et al.²⁷	190	800	133	21.1	6.8	14.3	8.3	66% at 18 months
Dasatinib	Cortes et al.²⁸ (imatinib R/I)	116	140	74	53	24	30	27	38% at 24 months
	Saglio et al.²⁹	214	140	149	28	18	25-28	14-21	7.8
	Talpaz et al.¹⁵	84	15-240	23	61	35	35	26	NA
Bosutinib second line (prior Imatinib only)	Gambacorti-Passerini et al.¹⁷	36	500		38	27	50	37	28% at 4 years
Bosutinib 3^r line		28			15	4	21	17	17% at 4 years
Ponatinib	Cortes et al.³⁰	62	45	52	29	NA	19	15	7

Abbreviations: BC, blast crisis; CCyR, complete cytogenetic response; CHR, complete hematological response; CML, chronic myeloid leukemia; CyR, cytogenetic response; HR, hematological response; MCyR, major cytogenetic response; NA, not applicable; TKI, tyrosine kinase inhibitor.

Imatinib is a first-generation TKI and clinical outcomes of imatinib monotherapy in BC remain unsatisfactory with most responses being transient. Pivotal trials that have investigated imatinib in BC are listed in Table 1. The recommended dose of imatinib in BC is 800 mg daily.

Dasatinib is a second-generation oral multitargeted TKI that is 325-fold more potent than imatinib. In a phase 1 study, imatinib-resistant or -intolerant patients treated with single-agent dasatinib showed impressive hematological and cytogenetic responses in advanced phase CML.¹⁵ In CML-BC, dasatinib at a dose of 140 mg once daily and 70 mg twice daily are equally efficacious, but the former is better tolerated.¹⁶

Nilotinib is a second-generation TKI that is more potent than imatinib. Most studies of nilotinib in CML-BC were done in patients intolerant or resistant to imatinib at a dose of 400 mg twice daily. Major adverse events to monitor while on nilotinib include hyperglycemia, pancreatitis, and vascular events. Nilotinib is approved in CP and AP-CML, but not in BC.

Bosutinib is a small molecule BCR::ABL and src TKI that is approved for all three phases of CML after prior treatment with a TKI. Patients treated with bosutinib in the second-line setting after failure of imatinib tend to have a much better response rate compared with those treated with bosutinib in the third line and beyond. The recommended dose in CML-BC is 500 mg once daily. Bosutinib does not have activity against T315I mutation.¹⁷

Ponatinib is an oral multitargeted third-generation pan BCR::ABL TKI that has impressive clinical activity in BC. Ponatinib is unique as it is the only TKI that can overcome the T315I mutation. It is recommended that patients who progress to BC on a second-generation TKI should be started on ponatinib rather than switching to a different second-generation TKI.¹⁸ The phase 2 PACE (Ponatinib Ph- positive acute lymphoblastic leukemia [ALL] and CML Evaluation) study evaluated ponatinib 45 mg daily in patients with all three phases of CML, including blast crisis (N = 62; myeloid blast crisis = 52). The median progression-free survival in patients with BC was 3.7 months and overall survival at 3 years was 9%¹⁹

Currently, data supporting use of asciminib in CML-BC are not available.

In summary, outcomes of single-agent TKIs in CML-BC remain unsatisfactory, and it should ideally be used as a “bridge” to get patients to a second CP and eventually to an allogenic SCT. Except nilotinib, all other TKIs are currently approved in CML-BC.

Combination Therapy: Chemotherapy plus TKI in Myeloid BC

Clinical outcomes tend to be better when TKIs are combined with chemotherapy rather than either treatment modalities used alone. Myeloid BC is usually treated with chemotherapy regimens for acute myeloid leukemia (AML) in combination with a second- or third-generation TKI, and this recommendation is endorsed by the European Leukemia Net.^31-33 In young fit patients, intensive chemotherapy (IC) plus TKI is an excellent induction regimen, whereas in elderly patients, hypomethylating agents (HMAs) in combination with a TKI is better tolerated. IC or HMA combined with TKI have a better response rate, lower relapse rate, and improved overall survival (OS) when compared with TKI alone.³⁴

(A) IC plus TKI:

Young patients with CML myeloid BC and good performance status can be treated with at combinations of TKIs and dose-intense chemotherapy. An overview of the studies is provided below and in Table 2.

Table 2.

Summary of studies showing outcomes of patients with myeloid BC treated with dose-intense chemotherapy plus TKI.

Study	Patients (N)	Chemotherapy	TKI	HR (%)	CHR (%)	CyR (%)	CCyR (%)	OS (months)
Fruehauf et al.³⁵	16	Mitoxantrone, etoposide, cytarabine	Imatinib 600 mg daily	81				6.4
Quintás-Cardama et al.³⁶	19	Low dose cytarabine (10 mg/day) and idarubicin	Imatinib 600 mg daily	74	47	21	15	5.7
Deau et al.³⁷	36	Daunorubicin, cytarabine	Imatinib 600 mg daily	77	55	41	30.5	16
Milojkovic et al.³⁸	4	FLAG-IDA	Dasatinib 100 mg daily	100		100	75	N/A
Copland et al.^39,40	17	FLAG-IDA	Ponatinib 15-45 mg daily	88	29		29	12

Abbreviations: BC, blast crisis; CCyR, complete cytogenetic response; CHR, complete hematological response; CyR, cytogenetic response; HR, hematological response; MCyR, major cytogenetic response; OS, overall survival; TKI, tyrosine kinase inhibitor; FLAG-IDA, fludarabine,cytarabine,granulocyte colony stimulating factor (G-CSF), idarubicin.

Fruehauf S et al reported a phase 1/2 trial of 16 patients with CML myeloid BC-treated imatinib in combination with mitoxantrone, etoposide, and cytarabine (MEC). Hematological response (HR) rate was 81% and median OS was 6.4 months.³⁵

Quintas Cardama et al reported a pilot study of 19 patients with CML myeloid BC who were treated with imatinib, low-dose cytarabine, and idarubicin. Fourteen patients (74%) achieved a HR and nine (47%) had a complete HR. Median survival was 5 months.³⁶

Deau et al conducted a dose escalation study of 36 patients with CML myeloid BC treated with standard 7 + 3 regimen consisting of daunorubicin combined with imatinib mesylate (600 mg/day) and cytarabine (200 mg/day for 7 days). A HR was observed in 28 patients (77.7%) with 20 (55.5%) achieving a complete HR. Median OS was 16 months and for those with a HR, it was 35.4 months³⁷

Milojkovic et al reported a small study of four patients who developed BC (myeloid-2, biphenotypic -1, lymphoid-1) on imatinib, and they were treated with a combination of dasatinib and FLAG-IDA (fludarabine, cytarabine, granulocyte colony-stimulating factor [G-CSF], and idarubicin). All patients achieved morphological remission and three of four had CCyR and MMR.³⁸

The MATCHPOINT phase 1/2 trial combined ponatinib with FLAG-IDA for patients in CML-BC. Eleven of 16 (69%) patients achieved a second CP after one cycle. Twelve of 17 (71%) patients proceeded to allogenic SCT. Three patients (18%) died from treatment-related toxicity. The 1-year OS was 45.8%.^39,40

A combination of cladribine, idarubicin, and cytarabine (CLIA) is highly effective in newly diagnosed AML patients aged ⩽ 65.⁴¹ Extrapolating data from the MATCHPOINT study, CLIA in combination with ponatinib could be a safe and effective regimen in CML myeloid blast crisis. A phase 2 study (NCT02115295) is currently investigating the role of CLIA regimen in combination with venetoclax in various myeloid neoplasms including CML myeloid BC.

(B) Older patients unfit for standard induction chemotherapy:

Older patients or those with comorbidities that preclude the use of dose-intense chemotherapy, can be treated with HMA-based regimens.

(i) HMA plus TKI

Abnormal DNA methylation of genes plays a crucial role in CML disease progression and resistance to TKIs.⁴² Hence, logically HMA in combination with TKIs could prove to be an effective therapeutic option in myeloid BC. In a retrospective study of 162 patients with CML myeloid BC treated with different chemotherapy regimens, HMA had a similar objective response rate (ORR) compared with IC. In elderly patients, HMA-based regimens achieved a better survival presumably due to better tolerance and lower induction mortality.^43,44 Some important trials that have shown encouraging activity of HMA and TKI in patients with CML myeloid BC are listed in Table 3.

Table 3.

Outcomes with HMA-based therapy with/without TKI.

Study	Patients (n)	Chemotherapy	TKI	Hematological Response		Cytogenetic Response		Median survival (months)
Study	Patients (n)	Chemotherapy	TKI	HR (%)	CHR (%)	CyR	CCyR	Median survival (months)
Kantarjian et al.⁴³	51	Decitabine 50-100 mg/m²	None	28	9	8	NA	5
Issa et al.⁴⁵	6	Decitabine 15 mg/m²daily for 5 days	None	50	17	33	NA	4
Oki et al.⁴⁶	10	Decitabine 15 mg/m²daily for 5 days × 2 weeks	Imatinib 600 mg daily	30	20	33	NA	3.5
Ghez et al.⁴⁷	5	Azacitidine 75 mg/m² for 7 days	Dasatinib or Nilotinib		100	80	40	24
Ruggiu et al.⁴⁸(retrospective review)	7	Azacitidine 75 mg/m² for 7 days	Dasatinib/Nilotinib/Ponatinib	40	NA	NA	42.9	28
Abaza et al.⁴⁹(phase 1/2)	18	Decitabine 10-20 mg/m² for 10 days	Dasatinib 100-140 mg	72	38	50	38	13.8
Saxena et al.³⁴(retrospective study)	20	Decitabine 20 mg/m² for 10 days	Dasatinib (N = 11), Imatinib (N = 7), Nilotinib (N = 1), Ponatinib (N = 1)	70	NA	NA	50	10.1

Abbreviations: CCyR, complete cytogenetic response; CHR, complete hematological response; CyR, cytogenetic response; HR, hematological response; HMA, hypomethylating agent; MCyR, major cytogenetic response; NA, not applicable; TKI, tyrosine kinase inhibitor.

(ii) Venetoclax plus TKI

Maiti et al investigated outcomes of patients with advanced Philadelphia-positive myeloid neoplasms (N = 9, myeloid BC) treated with venetoclax and various TKIs. The ORR in patients with myeloid BC was 75% (6/8), three patients achieved CCyR and four had minimal residual disease negative status. The median relapse-free survival was 3.9 months.⁵⁰ The synergistic activity of BCL-2 and BCR::ABL inhibition needs to be investigated further in larger studies.

Homoharringtonine-Based Regimens

Homoharringtonine (HHT), is a natural plant alkaloid with clinical activity in all phases of CML. Listed below are some clinical trial data looking at combinations of HHT and TKI in CML-BC.

In a phase 2 trial, 15 CML patients (BC, N = 9) in various phases of the disease (myeloid BC -3) were treated with HHT and Imatinib. The ORR was 40% at 4 months. Two patients with myeloid BC achieved CHR and one had CCyR. The median OS in the entire cohort was 4.6 months.⁵¹

Standard-dose imatinib combined with G-CSF and low-dose HHT was evaluated in a small study of 11 patients with CML myeloid BC who had failed imatinib therapy. The HR rate was 100% and seven (64%) achieved a CHR. MCyR and CCyR were 100% and 27%, respectively.⁵²

A phase 1/2 study evaluated subcutaneous HHT in patients with CML (myeloid BC, N = 8) who have failed imatinib therapy. HHT was found to be safe with all five evaluable patients achieving HR.⁵³ Response data were not available for patients with myeloid BC.

HHT in combination with cytarabine (HA regimen) is also an effective treatment option in myeloid BC. In a small study of 34 patients treated with HA regimen, the overall HR rate was 60% and 21% had a cytogenetic response.⁵⁴

HHT-based therapies appear promising and merit further investigation in combination with third-generation TKIs.

Novel and Emerging Therapies in CML Myeloid BC

Venetoclax-based regimens. BCL-2 is expressed on CML stem cells, and it has been shown in mice models that a combination of BCL-2 inhibitor and BCR::ABL TKI has synergistic properties and can eliminate the stem cells that are responsible for relapse.⁵⁵ A phase 2 clinical trial (NCT04188405) will investigate decitabine, venetoclax, and ponatinib in patients with Philadelphia-positive myeloid leukemias including CML myeloid BC.

Azacitidine (75 mg/m² daily for 7 days) is currently being investigated in combination with ponatinib (45 mg daily) in an open-label phase 2 study (Ponaza trial) (NCT03895671).

Janus kinase inhibitor (JAK). Preclinical studies have showed that HMA when combined with JAK1/JAK2 inhibitor (ruxolitinib) has synergistic properties.⁵⁶ A phase 2 study (N = 25, BC = 15) of decitabine plus ruxolitinib showed an ORR of 44% and median OS in the entire cohort was 9.5 months in patients with advanced MPN.⁵⁷

A phase 1b study is investigating the triplet combination of fludarabine, cytarabine and pegcrisantaspase in patients with relapsed/refractory leukemia including those with CML myeloid BC (NCT04526795).

Hu8F4, a monoclonal antibody targeting PR1/HLA-A2, is currently being investigated in patients with various advanced hematological malignancies including CML myeloid BC (NCT02530034)

A phase 1 study is investigating the role of HA-1T cell receptor T cell immunotherapy in patients with relapsed/refractory leukemia after allogenic SCT (NCT03326921).

Isocitrate dehydrogenase (IDH) inhibitor: Somatic mutations in IDH1 and IDH2 can be detected in patients with CML-BC and patients harboring these mutations could benefit from a targeted IDH1/IDH2 inhibitor added to TKI and chemotherapy.⁵⁸ Also, IDH2 inhibitor in combination with ruxolitinib is being investigated in a phase 2 clinical trial of accelerated and blast phase MPN (NCT04281498).

Gemtuzumab ozogamicin (GO), a CD33-targeted monoclonal antibody has been used successfully either as a single agent or combined with chemotherapy to achieve CHR and CCyR in patients with CD33-positive CML myeloid BC.⁵⁹ Jabbour et al reported that in heavily pretreated patients with myeloid neoplasms, including those with CML myeloid BC, cytarabine combined with twice daily fludarabine and GO could be an effective regimen achieving an ORR of 26% with a 21% CR.⁶⁰

Asciminib is a novel, first-in-class allosteric ABL myristoyl pocket inhibitor approved in patients with CP-CML that has failed two or more TKIs. The phase 3 ASCEMBL trial included 233 patients with CP-CML and MMR was 25.5% with asciminib and 13.2% with bosutinib. CCyR with asciminib and bosutinib was 40.8% and 24.2%, respectively.⁶¹ In ponatinib-naïve patients with T315I mutation, asciminib was able to achieve an MMR of 66.7% and in patients pretreated with ponatinib, the MMR dropped to 32.1%.⁶² Overall, asciminib is an exciting new drug with a unique mechanism of action and is more potent than most of the existing TKIs. A phase 1 study is investigating asciminib in combination with either imatinib or dasatinib or nilotinib in Philadelphia chromosome-positive myeloid neoplasm including myeloid BC (NCT02081378).

Vodobatinib, a novel third-generation BCR::ABL TKI is being investigated in a phase 1/2 study in treatment refractory CML (NCT02629692).

Olverembatinib (HQP1351) is a third-generation BCR::ABL TKI that is currently being investigated in a phase 2 study in combination with decitabine in patients with advanced CML (NCT05376852).

Allogenic SCT in CML-BC

Allogeneic SCT remains the only curative treatment option in patients with CML-BC. Pretransplant remission status determines post-allogenic SCT outcomes.⁶³ Niederwieser et al reported long-term outcomes of patients who received allogenic SCT for CML-BC (n = 96) and AP (n = 51). The OS at 15 years was 34% and the non-relapse mortality was 28%. Although the cumulative incidence of relapse post-SCT was 43%, there were no relapses beyond 5 years and this clearly establishes the role of SCT in achieving long-term leukemia-free survival. Patients with active BC at the time of SCT did poorly when compared with non-BC patients. Hence, it is critical to achieve a second CP prior to allogenic SCT. A summary of studies looking at outcomes of CML -BC patients who underwent allogenic SCT is provided in Table 4.⁶⁴

Table 4.

Summary of studies showing outcomes of patients who received allogenic SCT for CML-BC.

Study	Patients (N)	CML-BC (N)	Relapse (%)	3-year OS (%)	Treatment-related mortality (%)
Nicolini et al.⁶⁵	63	24	40	36	33
Khoury et al.⁶⁶	449	80	36	14	54
Radujkovic et al.⁶³	170	170	51	39	23
Niederwieser et al.⁶⁴	147	97	43	34	28

Abbreviations: BC, blast crisis; CML, chronic myeloid leukemia; OS, overall survival; SCT, stem cell transplantation.

In summary, the long-term outcomes in CML-BC with allogenic SCT remain poor. Treatment-related mortality and disease relapse remain the major barriers for improving outcomes. However, the outcomes are still better when compared with non-transplant options. There is an unmet need for novel therapies to reduce the relapse risk.

TKI maintenance post-allogenic SCT

Although endorsed by NCCN, the data supporting the use of post-allogenic SCT, TKI maintenance therapy is fairly limited.⁶⁷ Neiderweiser et al showed a significant survival benefit with TKI maintenance post-allogenic SCT in CML-BC.⁶⁴ BCR::ABL quantitative polymerase chain reaction (qPCR) should be monitored every 3 months for 2 years post-allogenic SCT.⁶⁸

Preventing BC in CML

As clinical outcomes of CML-BC remain suboptimal even in the current era, the emphasis should be to prevent progression to BC. A tailored treatment approach taking into account the disease risk, toxicity profile, comorbidities, and cost of TKIs is key to improving outcomes.⁶⁹ Figure 1 shows the algorithm for TKI selection in CP-CML and Figure 2 shows optimal response milestones. The treatment response can be monitored by serial measurements of BCR::ABL1 by qPCR in the peripheral blood. Patients who fail to achieve the milestones should be evaluated for drug resistance, compliance, and appropriate changes should be made.

Figure 1.

Algorithm for TKI selection in CP-CML. CML indicates chronic myeloid leukemia; CP, chronic phase; TKI, tyrosine kinase inhibitor.

Figure 2.

Optimal milestones in CML-CP therapy. CML indicates chronic myeloid leukemia; CP, chronic phase.

CML-CP patients with major-route ACAs have a poor response to TKIs and are at higher risk for disease progression to BC.⁷⁰ Also, patients with mutations in the ABL kinase domain of the Philadelphia chromosome have TKI resistance and they remain at high risk for blast transformation.⁷¹ Hence, patients with high-risk disease would benefit from early use of second- or third-generation TKI like ponatinib (known for pan BCR::ABL1 inhibition) and early allogenic SCT. Close monitoring for emerging mutations is required while on a TKI and appropriate therapeutic changes are essential to prevent progression to BC.

Choosing a TKI Based on the Mutational Profile

T315I mutation—ponatinib.

F317L/V/I/C, T315A mutations, V299L, nilotinib is preferred over dasatinib.^72-74

F359V/C/I, Y253H, E255K/V mutations, dasatinib is preferred over nilotinib.^75-77

The efficacy of dasatinib and nilotinib is likely similar in most other mutations.

Ponatinib is an option in all the above categories for patients previously treated with a TKI.

Conclusion

CML-BC is rare disease associated with poor outcomes. Figure 3 summarizes the currently treatment approach in CML myeloid BC. There is an unmet need for novel therapies that can achieve a second CP with low-induction mortality that will allow patients to proceed to an allogeneic SCT. Given the limited curative potential of existing therapies, the emphasis should be on prevention of BC.

Figure 3.

Current management in CML myeloid BC. BC indicates blast crisis; CML, chronic myeloid leukemia; CP, chronic phase; HMA, hypomethylating agent; SCT, stem cell transplantation; TKI, tyrosine kinase inhibitor; FLAG-IDA, fludarabine,cytarabine,granulocyte colony stimulating factor (G-CSF), idarubicin.

Footnotes

Declaration of conflicting interests:

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding:

The author(s) received no financial support for the research, authorship, and/or publication of this article.

Author Contributions

Binoy Yohanan: Concept, design, data collection and wrote the initial draft of the manuscript

Binsah George: Concept, design and revised the manuscript for important intellectual content.

ORCID iD

Binoy Yohanan

References

Kantarjian

Keating

Talpaz

, et al. Chronic myelogenous leukemia in blast crisis. Am J Med. 1987;83:445-454. doi:10.1016/0002-9343(87)90754-6.

Druker

Guilhot

O’Brien

, et al. Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med. 2006;355:2408-2417. doi:10.1056/NEJMoa062867.

Swerdlow

Campo

Pileri

, et al. The 2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood. 2016;127:2375-2390.

Johansson

Fioretos

Mitelman

. Cytogenetic and molecular genetic evolution of chronic myeloid leukemia. Acta Haematol. 2002;107:76-94. doi:10.1159/000046636.

Chereda

Melo

. Natural course and biology of CML. Ann Hematol. 2015;94:S107-S121. doi:10.1007/s00277-015-2325-z.

Perrotti

Jamieson

Goldman

Skorski

. Chronic myeloid leukemia: mechanisms of blastic transformation. J Clin Invest. 2010;120:2254-2264. doi:10.1172/JCI41246.

Makishima

Jankowska

McDevitt

, et al. CBL, CBLB, TET2, ASXL1, and IDH1/2 mutations and additional chromosomal aberrations constitute molecular events in chronic myelogenous leukemia. Blood. 2011;117:e198-e206. doi:10.1182/blood-2010-06-292433.

Javed

Lee

, et al. An integrative model of pathway convergence in genetically heterogeneous blast crisis chronic myeloid leukemia. Blood. 2020;135:2337-2353. doi:10.1182/blood.2020004834.

Chen

Medeiros

Kantajian

, et al. Differential depth of treatment response required for optimal outcome in patients with blast phase versus chronic phase of chronic myeloid leukemia. Blood Cancer J. 2017;7:e521. doi:10.1038/bcj.2017.4.

10.

Lambertenghi-Deliliers

Annaloro

Cortellaro

Pozzoli

Oriani

Polli

. Idarubicin in blastic crisis of chronic myelogenous leukemia. Haematologica. 1991;76:406-488.

11.

Iacoboni

Plunkett

Kantarjian

, et al. High-dose cytosine arabinoside: treatment and cellular pharmacology of chronic myelogenous leukemia blast crisis. J Clin Oncol. 1986;4:1079-1088. doi:10.1200/JCO.1986.4.7.1079.

12.

Radich

Dai

Mao

, et al. Gene expression changes associated with progression and response in chronic myeloid leukemia. Proc Natl Acad Sci U S A. 2006;103:2794-2799. doi:10.1073/pnas.0510423103.

13.

Soverini

Martinelli

Colarossi

, et al. Presence or the emergence of a F317L BCR-ABL mutation may be associated with resistance to dasatinib in Philadelphia chromosome–positive leukemia. J Clin Oncol. 2006;24:e51-e52. doi:10.1200/JCO.2006.08.9128.

14.

Chen

Cortes

Jorgensen

, et al. Differential impact of additional chromosomal abnormalities in myeloid vs lymphoid blast phase of chronic myelogenous leukemia in the era of tyrosine kinase inhibitor therapy. Leukemia. 2016;30:1606-1609. doi:10.1038/leu.2016.6.

15.

Talpaz

Shah

Kantarjian

, et al. Dasatinib in imatinib-resistant Philadelphia chromosome-positive leukemias. N Engl J Med. 2006;354:2531-2341. doi:10.1056/NEJMoa055229.

16.

Kantarjian

Cortes

Kim

, et al. Phase 3 study of dasatinib 140 mg once daily versus 70 mg twice daily in patients with chronic myeloid leukemia in accelerated phase resistant or intolerant to imatinib: 15-month median follow-up. Blood. 2009;113:6322-6329. doi:10.1182/blood-2008-11-186817.

17.

Gambacorti-Passerini

Kantarjian

Kim

, et al. Long-term efficacy and safety of bosutinib in patients with advanced leukemia following resistance/intolerance to imatinib and other tyrosine kinase inhibitors. Am J Hematol. 2015;90:755-768. doi:10.1002/ajh.24034.

18.

Andrews

Lipton

. The role of ponatinib in chronic myeloid leukemia in the era of treatment free remission. Leuk Lymphoma. 2019;60:3099-3101. doi:10.1080/10428194.2019.1665667.

19.

Cortes

Kim

Pinilla-Ibarz

, et al. Ponatinib efficacy and safety in Philadelphia chromosome-positive leukemia: final 5-year results of the phase 2 PACE trial. Blood. 2018;132:393-404. doi:10.1182/blood-2016-09-739086.

20.

Druker

Sawyers

Kantarjian

, et al. Activity of a specific inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome. N Engl J Med. 2001;344:1038-1042. doi:10.1056/NEJM200104053441402.

21.

Sawyers

. Imatinib induces hematologic and cytogenetic responses in patients with chronic myelogenous leukemia in myeloid blast crisis: results of a phase II study. Blood. 2002;99:3530-3539. doi:10.1182/blood.V99.10.3530.

22.

Kantarjian

Cortes

O’Brien

, et al. Imatinib mesylate (STI571) therapy for Philadelphia chromosome–positive chronic myelogenous leukemia in blast phase. Blood. 2002;99:3547-3553. doi:10.1182/blood.V99.10.3547.

23.

Wadhwa

Szydlo

Apperley

, et al. Factors affecting duration of survival after onset of blastic transformation of chronic myeloid leukemia. Blood. 2002;99:2304-2309. doi:10.1182/blood.V99.7.2304.

24.

Palandri

Castagnetti

Testoni

, et al. Chronic myeloid leukemia in blast crisis treated with imatinib 600 mg: outcome of the patients alive after a 6-year follow-up. Haematologica. 2008;93:1792-1796. doi:10.3324/haematol.13068.

25.

Giles

Kantarjian

le Coutre

, et al. Nilotinib is effective in imatinib-resistant or -intolerant patients with chronic myeloid leukemia in blastic phase. Leukemia. 2012;26:959-962. doi:10.1038/leu.2011.355.

26.

Kantarjian

Giles

Wunderle

, et al. Nilotinib in imatinib-resistant CML and Philadelphia chromosome-positive ALL. N Engl J Med. 2006;354:2542-2551. doi:10.1056/NEJMoa055104.

27.

Nicolini

Masszi

Shen

, et al. Expanding Nilotinib Access in Clinical Trials (ENACT), an open-label multicenter study of oral nilotinib in adult patients with imatinib-resistant or -intolerant chronic myeloid leukemia in accelerated phase or blast crisis. Leuk Lymphoma. 2012;53:907-914. doi:10.3109/10428194.2011.627480.

28.

Cortes

Rousselot

Kim

, et al. Dasatinib induces complete hematologic and cytogenetic responses in patients with imatinib-resistant or -intolerant chronic myeloid leukemia in blast crisis. Blood. 2007;109:3207-3213. doi:10.1182/blood-2006-09-046888.

29.

Saglio

Hochhaus

Goh

, et al. Dasatinib in imatinib-resistant or imatinib-intolerant chronic myeloid leukemia in blast phase after 2 years of follow-up in a phase 3 study: efficacy and tolerability of 140 milligrams once daily and 70 milligrams twice daily. Cancer. 2010;116:3852-3861. doi:10.1002/cncr.25123.

30.

Cortes

Kim

Pinilla-Ibarz

, et al. A phase 2 trial of ponatinib in Philadelphia chromosome-positive leukemias. N Engl J Med. 2013;369:1783-1796. doi:10.1056/NEJMoa1306494.

31.

Bonifacio

Stagno

Scaffidi

Krampera

di Raimondo

. Management of chronic myeloid leukemia in advanced phase. Front Oncol. 2019;9:1132. doi:10.3389/fonc.2019.01132.

32.

Hochhaus

Baccarani

Silver

, et al. European LeukemiaNet 2020 recommendations for treating chronic myeloid leukemia. Leukemia. 2020;34:966-984. doi:10.1038/s41375-020-0776-2.

33.

Hehlmann

Saußele

Voskanyan

Silver

. Management of CML-blast crisis. Best Pract Res Clin Haematol. 2016;29:295-307. doi:10.1016/j.beha.2016.10.005.

34.

Saxena

Jabbour

Issa

, et al. Impact of frontline treatment approach on outcomes of myeloid blast phase CML. J Hematol Oncol. 2021;14:94. doi:10.1186/s13045-021-01106-1.

35.

Fruehauf

Topaly

Buss

, et al. Imatinib combined with mitoxantrone/etoposide and cytarabine is an effective induction therapy for patients with chronic myeloid leukemia in myeloid blast crisis. Cancer. 2007;109:1543-1549. doi:10.1002/cncr.22535.

36.

Quintás-Cardama

Kantarjian

Garcia-Manero

, et al. A pilot study of imatinib, low-dose cytarabine and idarubicin for patients with chronic myeloid leukemia in myeloid blast phase. Leuk Lymphoma. 2007;48:283-289. doi:10.1080/10428190601075973.

37.

Deau

Nicolini

Guilhot

, et al. The addition of daunorubicin to imatinib mesylate in combination with cytarabine improves the response rate and the survival of patients with myeloid blast crisis chronic myelogenous leukemia (AFR01 study). Leuk Res. 2011;35:777-782. doi:10.1016/j.leukres.2010.11.004.

38.

Milojkovic

Ibrahim

Reid

Foroni

Apperley

Marin

. Efficacy of combining dasatinib and FLAG-IDA for patients with chronic myeloid leukemia in blastic transformation. Haematologica. 2012;97:473-474. doi:10.3324/haematol.2011.057513.

39.

Copland

Slade

Byrne

, et al. FLAG-IDA and ponatinib in patients with blast phase chronic myeloid leukaemia: results from the phase I/II UK trials acceleration programme matchpoint trial. Blood. 2019;134:497. doi:10.1182/blood-2019-125591.

40.

Copland

Slade

McIlroy

, et al. Ponatinib with fludarabine, cytarabine, idarubicin, and granulocyte colony-stimulating factor chemotherapy for patients with blast-phase chronic myeloid leukaemia (MATCHPOINT): a single-arm, multicentre, phase 1/2 trial. Lancet Haematol. 2022;9:e121-e132. doi:10.1016/S2352-3026(21)00370-7.

41.

Kadia

Cortes

Jabbour

, et al. Phase II study of cladribine, idarubicin, and cytarabine (araC) in patients with acute myeloid leukemia (AML). Blood. 2015;126:2541. doi:10.1182/blood.V126.23.2541.2541.

42.

Jelinek

Gharibyan

Estecio

, et al. Aberrant DNA methylation is associated with disease progression, resistance to imatinib and shortened survival in chronic myelogenous leukemia. PLoS One. 2011;6:e22110. doi:10.1371/journal.pone.0022110.

43.

Kantarjian

O’Brien

Cortes

, et al. Results of decitabine (5-aza-2’deoxycytidine) therapy in 130 patients with chronic myelogenous leukemia. Cancer. 2003;98:522-528. doi:10.1002/cncr.11543.

44.

Sacchi

Kantarjian

O’Brien

, et al. Chronic myelogenous leukemia in nonlymphoid blastic phase. Cancer. 1999;86:2632-2641. doi:10.1002/(SICI)1097-0142(19991215)86.

45.

Issa

JPJ

Gharibyan

Cortes

, et al. Phase II study of low-dose decitabine in patients with chronic myelogenous leukemia resistant to imatinib mesylate. J Clin Oncol. 2005;23:3948-3956. doi:10.1200/JCO.2005.11.981.

46.

Oki

Kantarjian

Gharibyan

, et al. Phase II study of low-dose decitabine in combination with imatinib mesylate in patients with accelerated or myeloid blastic phase of chronic myelogenous leukemia. Cancer. 2007;109:899-906. doi:10.1002/cncr.22470.

47.

Ghez

Micol

Pasquier

, et al. Clinical efficacy of second generation tyrosine kinase inhibitor and 5-azacytidine combination in chronic myelogenous leukaemia in myeloid blast crisis. Eur J Cancer. 2013;49:3666-3670. doi:10.1016/j.ejca.2013.07.147.

48.

Ruggiu

Oberkampf

Ghez

, et al. Azacytidine in combination with tyrosine kinase inhibitors induced durable responses in patients with advanced phase chronic myelogenous leukemia. Leuk Lymphoma. 2018;59:1659-1665. doi:10.1080/10428194.2017.1397666.

49.

Abaza

Kantarjian

Alwash

, et al. Phase I/II study of dasatinib in combination with decitabine in patients with accelerated or blast phase chronic myeloid leukemia. Am J Hematol. 2020;95:1288-1295. doi:10.1002/ajh.25939.

50.

Maiti

Franquiz

Ravandi

, et al. Venetoclax and BCR-ABL tyrosine kinase inhibitor combinations: outcome in patients with Philadelphia chromosome-positive advanced myeloid leukemias. Acta Haematol. 2020;143:567-573. doi:10.1159/000506346.

51.

Maiti

Cortes

Ferrajoli

, et al. Phase II trial of homoharringtonine with imatinib in chronic, accelerated, and blast phase chronic myeloid leukemia. Leuk Lymphoma. 2017;58:1-6. doi:10.1080/10428194.2017.1283030.

52.

Fang

Song

Han

Zhao

. Standard-dose imatinib plus low-dose homoharringtonine and granulocyte colony-stimulating factor is an effective induction therapy for patients with chronic myeloid leukemia in myeloid blast crisis who have failed prior single-agent therapy with imatinib. Ann Hematol. 2010;89:1099-1105. doi:10.1007/s00277-010-0991-4.

53.

Quintás-Cardama

Kantarjian

Garcia-Manero

, et al. Phase I/II study of subcutaneous homoharringtonine in patients with chronic myeloid leukemia who have failed prior therapy. Cancer. 2007;109:248-255. doi:10.1002/cncr.22398.

54.

Deng

Zho

Ding

Shi

. Homoharringtonine combined with cytarabine to treat chronic myelogenous leukemia in myeloid blast crisis and its impact on bone marrow CD34+CD7+ cells. Acta Haematol. 2014;132:172-176. doi:10.1159/000356742.

55.

Carter

Mak

, et al. Combined targeting of BCL-2 and BCR-ABL tyrosine kinase eradicates chronic myeloid leukemia stem cells. Sci Transl Med. 2016;8:355ra117. doi:10.1126/scitranslmed.aag1180.

56.

Rampal

Ahn

Abdel-Wahab

, et al. Genomic and functional analysis of leukemic transformation of myeloproliferative neoplasms. Proc Natl Acad Sci U S A. 2014;111:E5401-E5410. doi:10.1073/pnas.1407792111.

57.

Mascarenhas

Rampal

Kosiorek

, et al. Phase 2 study of ruxolitinib and decitabine in patients with myeloproliferative neoplasm in accelerated and blast phase. Blood Adv. 2020;4:5246-5256. doi:10.1182/bloodadvances.2020002119.

58.

Soverini

Score

Iacobucci

, et al. IDH2 somatic mutations in chronic myeloid leukemia patients in blast crisis. Leukemia. 2011;25:178-181. doi:10.1038/leu.2010.236.

59.

Weng

Huang

Lin

. Successful induction of hematologic and cytogenetic remission with gemtuzumab ozogamicin (mylotarg(R)) in patients with myeloid blast crisis of chronic myelogenous leukemia in refractory to imatinib mesylate and chemotherapy. Blood. 2005;106:4860. doi:10.1182/blood.V106.11.4860.4860.

60.

Jabbour

Garcia-Manero

Cortes

, et al. Twice-daily fludarabine and cytarabine combination with or without gentuzumab ozogamicin is effective in patients with relapsed/refractory acute myeloid leukemia, high-risk myelodysplastic syndrome, and blast- phase chronic myeloid leukemia. Clin Lymphoma Myeloma Leuk. 2012;12:244-251. doi:10.1016/j.clml.2012.03.003.

61.

Hochhaus

Boquimpani

Rea

, et al. Efficacy and safety results from ASCEMBL, a multicenter, open-label, phase 3 study of asciminib, a first-in-class STAMP inhibitor, vs bosutinib (BOS) in patients (Pts) with chronic myeloid leukemia in chronic phase (CML-CP) previously treated with ⩾2 tyrosine kinase inhibitors (TKIs). Blood. 2020;136:LBA-4. doi:10.1182/blood-2020-143816.

62.

Cortes

Hughes

Mauro

, et al. Asciminib, a first-in-class STAMP inhibitor, provides durable molecular response in patients (pts) with chronic myeloid leukemia (CML) harboring the T315I mutation: primary efficacy and safety results from a phase 1 trial. Blood. 2020;136:47-50. doi:10.1182/blood-2020-139677.

63.

Radujkovic

Dietrich

Blok

, et al. Allogeneic stem cell transplantation for blast crisis chronic myeloid leukemia in the era of tyrosine kinase inhibitors: a retrospective study by the EBMT chronic malignancies working party. Biol Blood Marrow Transplant. 2019;25:2008-2016. doi:10.1016/j.bbmt.2019.06.028.

64.

Niederwieser

Morozova

Zubarovskaya

, et al. Risk factors for outcome after allogeneic stem cell transplantation in patients with advanced phase CML. Bone Marrow Transplant. 2021;56:2834-2841. doi:10.1038/s41409-021-01410-x.

65.

Nicolini

Modolo

Raus

, et al. Allogeneic stem cell transplantation for blast crisis (BC) chronic myelogenous leukemia (CML) in the tyrosine kinase inhibitors (TKIs) era. Analysis of pre-transplant variables on transplant outcome. On behalf of the Societe Française De Greffe De Moelle Et De Therapie Cellulaire and the French Group of CML. Blood. 2010;116:2266. doi:10.1182/blood.V116.21.2266.2266.

66.

Khoury

Kukreja

Goldman

, et al. Prognostic factors for outcomes in allogeneic transplantation for CML in the imatinib era: a CIBMTR analysis. Bone Marrow Transplant. 2012;47:810-816. doi:10.1038/bmt.2011.194.

67.

Lübking

Dreimane

Sandin

, et al. Allogeneic stem cell transplantation for chronic myeloid leukemia in the TKI era: population-based data from the Swedish CML registry. Bone Marrow Transplant. 2019;54:1764-1774. doi:10.1038/s41409-019-0513-5.

68.

Deininger

Shah

Altman

, et al. Chronic myeloid leukemia, version 2.2021, NCCN clinical practice guidelines in oncology. J Natl Compr Canc Netw. 2020;18:1385-1415. doi:10.6004/jnccn.2020.0047.

69.

Ciftciler

Haznedaroglu

. Tailored tyrosine kinase inhibitor (TKI) treatment of chronic myeloid leukemia (CML) based on current evidence. Eur Rev Med Pharmacol Sci. 2021;25:7787-7798. doi:10.26355/eurrev_202112_27625.

70.

Fabarius

Leitner

Hochhaus

, et al. Impact of additional cytogenetic aberrations at diagnosis on prognosis of CML: long-term observation of 1151 patients from the randomized CML Study IV. Blood. 2011;118:6760-6768. doi:10.1182/blood-2011-08-373902.

71.

Soverini

Martinelli

Rosti

, et al. ABL mutations in late chronic phase chronic myeloid leukemia patients with up-front cytogenetic resistance to imatinib are associated with a greater likelihood of progression to blast crisis and shorter survival: a study by the GIMEMA working party on chronic myeloid leukemia. J Clin Oncol. 2005;23:4100-4109. doi:10.1200/JCO.2005.05.531.

72.

Soverini

Martinelli

Colarossi

, et al. Second-line treatment with dasatinib in patients resistant to imatinib can select novel inhibitor-specific BCR-ABL mutants in Ph+ ALL. Lancet Oncol. 2007;8:273-274. doi:10.1016/S1470-2045(07)70078-5.

73.

Soverini

Colarossi

Gnani

, et al. Resistance to dasatinib in Philadelphia-positive leukemia patients and the presence or the selection of mutations at residues 315 and 317 in the BCR-ABL kinase domain. Haematologica. 2007;92:401-404. doi:10.3324/haematol.10822.

74.

Cortes

Jabbour

Kantarjian

, et al. Dynamics of BCR-ABL kinase domain mutations in chronic myeloid leukemia after sequential treatment with multiple tyrosine kinase inhibitors. Blood. 2007;110:4005-4011. doi:10.1182/blood-2007-03-080838.

75.

Soverini

Gnani

Colarossi

, et al. Philadelphia-positive patients who already harbor imatinib-resistant Bcr-Abl kinase domain mutations have a higher likelihood of developing additional mutations associated with resistance to second- or third-line tyrosine kinase inhibitors. Blood. 2009;114:2168-2171. doi:10.1182/blood-2009-01-197186.

76.

Hughes

Saglio

Branford

, et al. Impact of baseline BCR-ABL mutations on response to nilotinib in patients with chronic myeloid leukemia in chronic phase. J Clin Oncol. 2009;27:4204-4210. doi:10.1200/JCO.2009.21.8230.

77.

Soverini

Hochhaus

Nicolini

, et al. BCR-ABL kinase domain mutation analysis in chronic myeloid leukemia patients treated with tyrosine kinase inhibitors: recommendations from an expert panel on behalf of European LeukemiaNet. Blood. 2011;118:1208-1215. doi:10.1182/blood-2010-12-326405.

Current Management of Chronic Myeloid Leukemia Myeloid Blast Phase

Abstract

Keywords

Introduction

Mechanism of Progression to CML Blast Crisis

Management of Myeloid BC

Single-Agent TKI in CML Myeloid BC

Combination Therapy: Chemotherapy plus TKI in Myeloid BC

(A) IC plus TKI:

(B) Older patients unfit for standard induction chemotherapy:

(i) HMA plus TKI

(ii) Venetoclax plus TKI

Homoharringtonine-Based Regimens

Novel and Emerging Therapies in CML Myeloid BC

Allogenic SCT in CML-BC

TKI maintenance post-allogenic SCT

Preventing BC in CML

Choosing a TKI Based on the Mutational Profile

Conclusion

Footnotes

Declaration of conflicting interests:

Funding:

Author Contributions

ORCID iD

References